title: Programmed death-1 (PD-1)-dependent functional impairment of CD4(+) T cells in recurrent genital papilloma.
abstract: Genital papilloma is caused by human papilloma virus (HPV) infection and recurs frequently. Although T cells are known to play a critical role in the control of HPV infection and papilloma development, the function and phenotype of these cells in the lesion remain to be elucidated. In the present study, we examined the function and phenotype of CD4(+) T cells isolated from the lesions of primary (n = 9) and recurrent (n = 11) genital papillomas. In recurrent papillomas, the frequency of proliferating (Ki-67(+)) CD4(+) T cells was significantly reduced compared with primary papillomas. Cytokine production was evaluated by intracellular cytokine staining in anti-CD3/anti-CD28-stimulated CD4(+) T cells. CD4(+) T cells from recurrent lesions showed impaired production of IL-2, IFN-γ, and TNF-α. Of interest, the frequency of cytokine-producing CD4(+) T cells significantly correlated with the frequency of Ki-67(+)CD4(+) T cells. We also studied expression of programmed death-1 (PD-1), a T-cell exhaustion marker. The frequency of PD-1(+)CD4(+) T cells was significantly increased in recurrent lesions and inversely correlated with the frequency of cytokine-producing CD4(+) T cells. The functional significance of PD-1 expression was determined in blocking assays with anti-PD-L1, which restored cytokine production of CD4(+) T cells from recurrent lesions. Taken together, in recurrent genital papilloma lesions, proliferation, and cytokine production by CD4(+) T cells are impaired and the PD-1/PD-L1 interaction is responsible for the functional impairment of CD4(+) T cells.
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon, 305-701, Republic of Korea.
authors.forename: Dong-Yeop
authors.initials: DY
authors.lastname: Chang
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Song
authors.forename: Sooseong
authors.initials: S
authors.lastname: You
authors.forename: Jino
authors.initials: J
authors.lastname: Lee
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Vito
authors.initials: V
authors.lastname: Racanelli
authors.forename: Hwancheol
authors.initials: H
authors.lastname: Son
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
mesh_terms: D000328:Adult; D060890:B7-H1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D049109:Cell Proliferation; D003218:Condylomata Acuminata / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis* / Q000037:antagonists & inhibitors; D012008:Recurrence
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D019394:Ki-67 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor